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J Biol Chem, Vol. 275, Issue 16, 12136-12146, April 21, 2000
The Lipophilicity of Phorbol Esters as a Critical Factor in
Determining the Pattern of Translocation of Protein Kinase C Fused to Green Fluorescent Protein*
Qiming J.
Wang ,
Tzan-Wei
Fang ,
David
Fenick ,
Susan
Garfield§,
Bruno
Bienfait¶,
Victor E.
Marquez¶, and
Peter M.
Blumberg
From the Molecular Mechanisms of Tumor Promotion
Section, Laboratory of Cellular Carcinogenesis and Tumor Promotion,
§ Laboratory of Experimental Carcinogenesis, and
¶ Laboratory of Medicinal Chemistry, NCI, National Institutes of
Health, Bethesda, Maryland 20892
Our previous study showed differential
subcellular localization of protein kinase C (PKC) by phorbol
esters and related ligands, using a green fluorescent protein-tagged
construct in living cells. Here we compared the abilities of a series
of symmetrically substituted phorbol 12,13-diesters to translocate PKC
. In vitro, the derivatives bound to PKC with similar
potencies but differed in rate of equilibration. In vivo,
the phorbol diesters with short, intermediate, and long chain fatty
acids induced distinct patterns of translocation. Phorbol
12,13-dioctanoate and phorbol 12,13-nonanoate, the intermediate
derivatives and most potent tumor promoters, showed patterns of
translocation typical of phorbol 12-myristate 13-acetate, with plasma
membrane and subsequent nuclear membrane translocation. The more
hydrophilic compounds (phorbol 12,13-dibutyrate and phorbol
12,13-dihexanoate) induced a patchy distribution in the cytoplasm,
more prominent nuclear membrane translocation, and little plasma
membrane localization at all concentrations examined (100 nM to 10 µM). The highly lipophilic
derivatives, phorbol 12,13-didecanoate and phorbol
12,13-diundecanoate, at 1 µM caused either plasma
membrane translocation only or no translocation at incubation times up
to 60 min. Our results indicate that lipophilicity of phorbol esters is
a critical factor contributing to differential PKC localization and
thereby potentially to their different biological activities.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Bldg. 37, Rm.
3A01, NCI, National Institutes of Health, 37 Convent Dr. MSC 4255, Bethesda, MD 20892-4255. Tel.: 301-496-3189; Fax: 301-496-8709; E-mail:
blumberp@dc37a.nci.nih.gov.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 2000 by the American Society for Biochemistry and Molecular Biology.
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